CZ301070B6 - Telmisartan tablets - Google Patents

Abstract

In the present invention, there is disclosed a composition containing an active substance called telmisartan and consisting of granules of a telmisartan mixture, in which granules, the active substance is present in the form of alkali salts. The granules further include an organic or inorganic base being selected from the group consisting of meglumine, sodium or potassium hydroxide, optionally a mixture of these bases, a binding agent, most preferably polyvinyl pyrrolidone, sorbitol, optionally other adjuvants; in addition to the above-described granules, the composition further comprises sorbitol particles, optionally other adjuvants, wherein the size of 99 percent by weight of all particles of the telmisartan mixture is smaller than 1.0 mm and 95 percent by weight of sorbitol particles included in the composition both inside and outside the telmisartan mixture granules is smaller than 0.250 mm.

Description

The invention relates to a solid pharmaceutical composition of telmisartan.

BACKGROUND OF THE INVENTION

According to WO 00/27397, the spray dried granulate of telmisartan is mixed with sorbitol with the granid of lacidipine, after addition of the lubricant the mixture is tabletted.

US 2005/0089575 A1 addresses the issue of the compatibility of telmisartan and hydrochlorothiazide. She sees the most advantageous solution in layered tablets. The first layer is amorphous sodium telmisartan and the second is hydrochlorothiazide (or diuretic in general). These layered tablets make it possible to solve both the poor solubility of telmisartan and the need for immediate release

HCTZ.

According to the document, the telmisartan layer is prepared by preparing an aqueous solution of telmisartan together with a base and a solubilizer. This is followed by spray drying of this solution to obtain a spray-dried granulate. Finally, the granulate is mixed with the fillers and the lubricant.

The hydrochlorothiazide layer is prepared by mixing and granulating HCTZ with the tablet disintegrating components.

The premixes are tableted into a layered tablet by a known method.

According to WO 04/028505, a surfactant, especially a poloxamer, is added to the composition to further improve the telmisartan formulation. Spray drying of telmisartan either alone or by spraying telmisartan onto a solid carrier, such as a sugar alcohol, is again used.

The known method of solving a pharmaceutical composition with telmisartan can be summarized in the spray drying step of the telmisartan solution and the base alone or with the addition of a solid diluent and the mixing step with the other ingredients. When using other active substances, an additional granulate of this substance is always used which is either mixed with telmisartan granulate or tableted in a layered tablet.

Unfortunately, it turns out that using known specific embodiments of this generally loaded process, the rate of release of the active ingredient varies from case to case, or even from batch to batch.

SUMMARY OF THE INVENTION The object of the present invention was to provide a process for the preparation of a tablet containing telmisartan with an optional further active ingredient which allows reproducible properties of the product over a wide dose range of the active ingredient.

SUMMARY OF THE INVENTION

BACKGROUND OF THE INVENTION The present invention relates to a telmisartan active ingredient composition comprising granules of a tartrate mixture wherein the active ingredient is in the form of alkali salts, an organic or inorganic base selected from meglumine, sodium or potassium hydroxide, or a mixture of these bases, a binder , preferably polyvinylpyrrolidone, sorbitol, optionally other excipients; furthermore, the composition contains sorbitol particles or other excipients outside the granules, wherein:

99 wt. % of all particles of the telmisartan mixture has a diameter of less than 1.0 mm and 95 wt.

. and.

all of the sorbitol particles contained in the composition inside and outside the granules of the telmisartan mixture have a diameter of less than 0.250 mm.

In a preferred embodiment, 70 to 80 wt. The granules of the telmisartan mixture have a diameter in the range of 0.1 to 0.8 mm, and 60 to 70% by weight of the sorbitol particles contained in the composition have a diameter of less than 0.125 mm.

Another factor affecting the rate of release of the active agent is the particle size of the active agent. Obviously, the more uniform the distribution of this size, the more reproducible it is to relax. In the case of the telmisartan composition according to the invention, it has been found that telmisartan in the range of 0.5 to 5 µm, which may form clusters, but not more than pm, is most preferred.

For a particularly preferred embodiment, PVP (polyvinylpyrrolidone; Povidone) 25 is further selected in an amount of 8.3% by weight based on the total composition.

The present invention also relates to a process for the preparation of this composition comprising dissolving telmisartan in a sodium or potassium hydroxide solution, adding a given amount of PVP and spraying the solution onto the fluid bed of sorbitol.

Detailed description of the invention:

Although the composition of telmisartan is known, it has always been a problem to find such parameters of the composition that give reproducible results of the rate of release of the active substance (dissolution). It has been shown in experiments that, even with the same composition of the composition, while maintaining the same procedure, the properties, especially the release rate of the active substance, significantly change from batch to batch.

The rate of drug release (dissolution) is one of the major factors influencing the concentratory profile of the plasma concentrations of the drug. This factor is also associated with the bioavailability of the drug, that is, a proportion of the total dose absorbed by the organism.

Thus, ensuring the reproducibility of the release of the active ingredient is an absolutely essential task of developing the composition.

However, once reproducibility of dissolution has been ensured, it should be adjusted to a level that maintains an effective concentration in blood plasma throughout the two doses. Furthermore, it must be ensured that this concentration does not in any case exceed a threshold that could adversely affect the patient.

Thus, the second task is to accurately determine at what rate the substance is to be released from the composition and how to accurately ensure this release.

Thus, the composition of the invention is determined by parameters that result in maintaining the reproducibility of the dissolution, and preferably those parameters that provide specific dissolution and respiration values. its time dependence to achieve the desired final effect.

It was found that to achieve the desired effect it is necessary to prepare such a composition, which, when conditions described in Pharm. Eur., Basket assembly method at 100 RPM ^one achieved with the following values:

-2CL, «JV.LV/V 1- * V

In acidic environments of 0.0M HCl, the limits must be met:

Time dissolved active substance [min] [%] 15 Dec 25-55 30 55-85 45 > 85

and in phosphate buffer medium at pH 6.8

Time dissolved active substance [min] [%] 15 Dec 45-75 30 > 80

An obvious parameter for the rate of dissolution of any substance is its surface area, given the particle size of the drug. The smaller the particles, the larger the surface they provide and can reasonably be expected to dissolve faster. Therefore, it is clear and it is not explicitly stated in the description of the invention that all parameters have to be maintained at a constant particle size of the active substance.

Surprisingly, it has been shown that the size of the granules in which telmisartan is found is an essential parameter to ensure reproducibility of dissolution. Virtually all granules must be less than 1 mm.

The second condition for reproducibility of dissolution is the size of the free particles of sorbitol in the composition. These must be practically all smaller than 0.250 mm.

However, it has been shown that, in order to improve the other properties of the composition, it is preferred that the granules of the telmisartan mixture be spread in an OO size of up to 0.8 mm from about ³ Λ of the total weight. Similarly, for free sorbitol, it is preferred that its particles be less than about 0.125 mm from about 2/3 of the weight of the feed.

The weight fractions of the individual particle sizes are determined by sieve analysis, the results of which are described in more detail in the examples below.

In a preferred embodiment, the active ingredient is located in the intragranular space. In particular, the granules are combined with a solution comprising a PVP binder, an alkaline salt of telmisartan and an alkaline hydroxide or meglumine. In terms of other product properties, the composition where meglumine is outside the granules of the telmisartan mixture has proven more advantageous.

The method of preparing the composition described below, i.e. spraying the active ingredient onto a solid carrier, is known in that a relatively narrow particle distribution can be obtained, which can be adjusted by the parameters of the device.

However, in the case of a given telmisartan mixture, it appears that the active agent particles tend to form clusters. It appears that, for the desired dissolution, particle sizes of 0.5 to 5 are preferred

-3GB 301070 B6 pm, with clumps less than 50 pm. The usual setting is a particle of about 2 μιη and clusters of 30 to μιη. It will be appreciated that the composition of the present invention can exhibit the desired dissociation even at other particle size / aggregate ratios.

Determination of the particle size of the active substance in the granulate can be carried out by Raman or IR spectroscopy, in particular by a method known as mapping.

In the course of the development of the composition according to the invention, it has further been found that the PVP binder used has a significant effect on the final dissolution of the active substance. Various types of PVP can also be used for successful parameter setting. However, it is necessary to determine the quantity separately for each of them. Polyvinylpyrrolidone - PVP 25, PVP 30 or PVP 90, i.e. having a molecular weight of about 30,000, is suitable,

000, respectively. In the case of using PVP 25, 30 or 90, the values are in the range of 2 to 10% by weight. PVP of type 25 is shown to be advantageous in an amount of 6 to 10%, particularly preferably in an amount of 8.3 ± 0.5% by weight.

Method of production:

Telmisartan is dissolved in water, preferably water / ethanol, in the presence of a base such as NaOH, KOH, meglumine and the like, preferably only NaOH, and a binder which is PVP, which serves not only as a binder but also as a solution stabilizer . Sorbitol is fluidically granulated with this solution. The dried and sieved granulate is mixed with a portion of the soluble filler, sorbitol and other excipients such as meglumine or magnesium stearate.

Specific fluid process parameters such as temperatures of the inlet fluid (e.g., air), the feed rate of the telmisartan solution onto the fluidized bed, or the particle size to be injected need to be set according to the particular fluidized bed granulation device. Examples of specifically selected granule parameters are given below, but are not applicable to each device; serve only to illustrate the invention. An essential parameter to be observed in any such device is the particle size of the sorbitol prior to initiation of the granule. These particles must be practically all less than 250 µm, and are preferably less than 0.125 mm in about 2/3.

DETAILED DESCRIPTION OF THE INVENTION

In all of the examples below, sorbitol in particles was used to prepare the composition, of which 98% by weight was less than 0.250 mm and 67% was less than 0.1 mm.

Composition A: Telmisartan 80 mg tbl.

Ingredients mg / tbl. Telmisartan 80.0 Sodium hydroxide 6.8 Povidone 40.0 Sorbitol 324.4 Meglumin 24.0 Magnesium stearate 4.8 Total core weight 480.0

-4 LZ JU1U / U DO

The total batch was 10 kg.

Telmisartan was dissolved in a solution of NaOH and povidone. Sorbitol was granulated fluidly in this way. The granulation was carried out in a WSG 15 with an average feed rate of g / min.kg of sorbitol, at an inlet air temperature of 47-55 ° C and a product temperature of 30-40 ° C. The resulting granulate was fluid-dried. After drying, the granulate was sieved and then mixed with the remaining amount of sorbitol, meglumine and magnesium stearate. The cores weighing 480 mg were compressed from the thus formed tablet. The cores produced in this way released 39% of the active substance in 15.01M HCl in a 0.01 M dissolution device, 72% of the active substance in 15 minutes and 95% after 45 minutes.

The granulate produced according to the above procedure gave the following sieve analysis;

Size [mm] <0.1 0,1-0,25 0,25-0,5 0,5-0,8 0.8-1.0 > 1.0 Proportion [% by weight] 8.3 10.4 32.4 39.7 9.1 0.2

Composition B: Telmisartan 80 mg tbl.

Ingredients mg / tbl. Telmisartan 80.0 Sodium hydroxide 6.8 Povidone 40.0 Sorbitol 348.4 Meglumin 0 Magnesium stearate 4.8 Total core weight 480.0

The total batch was 1 kg.

Telmisartan was dissolved in a solution of NaOH and povidone. Sorbitol was fluidically granulated in this solution. The granulation took place in an Aeromatic MP1; the average feed rate was

21 g / min.kg of sorbitol, at an inlet air temperature of 47-55 ° C and a product temperature of 33-34 ° C. The resulting granulate was fluid-dried. After drying, the granulate was sieved and then mixed with the remaining amount of sorbitol and magnesium stearate. The cores weighing 480 mg were compressed from the thus formed tablet. The cores thus produced released 26% of the active ingredient in the dissolution apparatus of Ph.Eur., In 0.01 M HCl after 15 minutes, 44% of active ingredient after 30 minutes and 57% of active ingredient after 45 minutes.

-5GB 301070 B6

Granulate size after sieving:

Size [mm] <0.1 0,1-0,25 0,25-0,5 0,5-0,8 0.8-1.0 > 1.0 Proportion [% by weight] 10.2 34.8 47.6 7.2 0.2 0

Composition C: Telmisartan 80 mg tbl.

Ingredients mg / tbl. Telmisartan 80.0 Sodium hydroxide 6.8 Povidone 40.0 Sorbitol 343.6 Meglumin 4.8 Magnesium stearate 4.8 Total core weight 480.0

The total batch was 1 kg.

Telmisartan was dissolved in a solution of NaOH and povidone. Sorbitol was fluidically granulated in this solution. The granulation took place in an Aeromatic MP1; the average feed rate was 18 g / min.kg of sorbitol, at an inlet air temperature of 47-55 ° C and a product temperature of 35-36 ° C. The resulting granulate was fluid-dried. After drying, the granulate was sieved and then mixed with the remaining amount of sorbitol, meglumine and magnesium stearate. The cores weighing 480 mg were compressed from the thus formed tablet. The cores thus produced released 30% of the active ingredient in 0.01 M HCl in 0.01 M HCl after 15 minutes, 52% of active ingredient after 30 minutes and 69% of active ingredient after 45 minutes.

Granulate size after sieving:

Size [mm] <0.1 0,1-0,25 0,25-0,5 0,5-0,8 0.8-1.0 > 1.0 Proportion [% by weight] 13.6 52.4 32.6 1,2 0.2 0

-ήVZj JU1U / U DO

Claims (14)

1. A solid pharmaceutical composition of telmisartan comprising granules of telmisartan mixture in which the active ingredient is in the form of alkali salts, an organic or inorganic base selected from the group consisting of meglumine, sodium hydroxide and potassium hydroxide and mixtures thereof, a binder, in particular polyvinylpyrrolidone-PVP, sorbitol and optionally other excipients; and the composition further comprises sorbitol particles, optionally further excipients, outside the granules, wherein 99 wt. % of all granules of the telmisartan mixture has a diameter of less than 1.0 mm and 98 wt. the total sorbitol particles, both in and outside the granules of the telmisartan mixture, is less than 0.250 mm. Pharmaceutical composition according to claim 1, characterized in that 70 to 80% 15 wt. The granules of the telmisartan mixture have a diameter in the range of 0.1 to 0.8 mm and 67 wt. The sorbitol particles have a diameter of less than 0.1 mm. Pharmaceutical composition according to claim 1 or 2, characterized in that the telmisartan mixture consists of sorbitol particles which are combined into a granulate with a solution of telmisart20 new salt and a binder and a base formed by sodium or potassium hydroxide, optionally in admixture with meglumine. Pharmaceutical composition according to claim 3, characterized in that PVP 25, PVP 30 or PVP 90 in an amount of 2 to 10 wt. Pharmaceutical composition according to claim 4, characterized in that PVP 25 in an amount of 6 to 10 wt. Pharmaceutical composition according to claim 5, characterized in that it is an amount 30 PVP 25 selected in the range 8.3 ± 0.5 wt. Pharmaceutical composition according to any one of claims 3 to 6, characterized in that it contains granules of a telmisartan mixture comprising a telmisartan salt having a particle diameter of 0.5 to 5 gm, which do not form clusters greater than 50 gm. Pharmaceutical composition according to any one of claims 3 to 7, characterized in that the telmisartan mixture comprises sodium or potassium hydroxide inside the granules, while meglumine outside the granules. 40 A process for producing a composition according to any one of claims 1 to 8, comprising preparing a telmisartan mixture comprising injecting a solution of telmisartan in water, optionally a mixture of water and ethanol, sodium or potassium hydroxide, a binder, and optionally meglumine onto a fluid bed of sorbitol, the dried granulate is mixed with another portion of sorbitol, optionally with meglumine, and other excipients. 10. The process of claim 9 wherein the meglumine is not present in the injected telmisartan solution, but is admixed to the finished granulate of the telmisartan mixture. 50 Method according to claim 9 or 10, characterized in that a lubricant selected from salts of stearic acid, talc or colloidal silica is added to the granulate. -7EN 301070 B6 A process according to any one of claims 9 to 11, characterized in that 0.5 to 3 wt. % sodium or potassium hydroxide and 10 to 20 wt. % of telmisartan, and further injected or added to the finished granulate 1 to 10 wt. meglumine, and 0.5 to 3% 5 wt. magnesium stearate, based on the final weight of the composition. The process according to claim 12, wherein 1 to 2 wt. % sodium or potassium hydroxide, 4 to 8 wt. % meglumine, 10 to 20 wt. % telmisartan, and 0.8 to 2.5 wt. magnesium stearate, based on the final weight of the composition. 15 End of Document. 8 -